Review: The central role of the gut microbiota in the pathophysiology and management of type 2 diabetes. Image Credit: nobeastsofierce / Shutterstock
In a recent review published in the journal Cell Host & Microbe, researchers discussed the role of gut microbiota in type 2 diabetes mellitus (T2DM), specifically focusing on the microbial strains, diet-derived metabolites, and their complex, and how these contribute to the disease's multifactorial nature.
Additionally, they explored potential diagnostic and therapeutic strategies involving the gut microbiota for personalized T2DM management, highlighting the challenges in establishing causality and the variability in patient responses to these interventions.
Background
The global prevalence of T2DM is increasing, with factors like socio-economic changes, environment, and genetics contributing. Recent research has highlighted the multifactorial nature of T2DM, expanding our understanding from early models to the more comprehensive "egregious eleven" pathways, with the gut microbiome now recognized as a critical factor.
The understanding of T2DM's pathophysiology has expanded from early models to include eleven pathways, with the gut microbiome now recognized as a key factor.
Advances in sequencing technologies have shown the gut microbiome's influence on metabolism and T2DM development. Industrialization, medication use, and Western lifestyles have reduced gut microbial diversity, possibly leading to increased T2DM rates. This reduction in diversity, characterized by the loss of key bacterial species, may contribute to chronic inflammation and T2DM, though proving causality remains challenging.
In the present review, researchers explored current evidence on gut homeostasis, its role in diabetes pathogenesis, the impact of gut microbiota on antidiabetic drugs, and potential microbiota-centered therapies for diabetes.
Disruption of gut homeostasis in diabetes
In patients with T2DM, gut microbiota composition often shifts towards increased facultative anaerobic bacteria, reduced diversity, and fewer beneficial obligate anaerobes, a state known as dysbiosis. This dysbiosis is not uniform across all patients but varies significantly due to factors such as diet, medication, and immune health, which may contribute to disease progression in different ways.
Maintaining gut homeostasis— characterized by a healthy microbial community, strong intestinal barrier, and appropriate immune responses— is crucial for preventing metabolic diseases.
Gut microbes produce key metabolites like short-chain fatty acids (SCFAs) and bile acids that are vital for host health, and disruption in their production is linked to diabetes. Therefore, addressing dysbiosis and promoting gut homeostasis involves more than altering the microbial composition; it requires a holistic approach that considers the patient's diet, lifestyle, and immune status.
Alterations in gut microbiota composition along the GI tract in diabetes
Evidence suggests that T2DM patients often exhibit altered gut microbiota, including reduced diversity, increased facultative anaerobic bacteria, and a decline in beneficial butyrate-producing bacteria.
These changes, termed dysbiosis, vary significantly among individuals and are influenced by factors like diet, medication, and immune health.
Some bacterial strains, like Prevotella copri, have been shown to exhibit complex and sometimes contradictory associations with metabolic outcomes, underscoring the importance of individualized approaches in understanding these relationships.
T2DM is also linked to disrupted daily oscillations in gut microbiota, which may contribute to metabolic disorders. However, the reliance on fecal samples in most studies presents limitations, as these samples may not fully capture the microbial diversity across different regions of the gastrointestinal tract.
Comprehensive gut sampling, across different intestinal regions, is essential to better understand these dynamics in T2DM.
Chronic low-grade inflammation due to microbiota alterations further impacts host metabolism and promotes the growth of pathogens. Microbial metabolites produced in the gut significantly influence systemic physiology, particularly through interactions with the liver, highlighting the need for comprehensive gut sampling to better understand these dynamics in T2DM.
The gut microbiota as a causal mediator in the "egregious eleven"
In the β cell-centric model, hyperglycemia is viewed as the final stage of diabetes, explaining the various organ and system dysfunctions in diabetes, including insulin resistance (IR) and systemic inflammation.
Gut microbiota plays a crucial role in these processes, influencing β cell function, metabolism, and inflammation through the production of key microbial metabolites such as SCFAs and branched-chain amino acids (BCAAs).
Elevated BCAAs are linked to IR and T2DM, while bile acids and other microbial products affect glucose and lipid metabolism. Inflammation, driven by lipopolysaccharide from gut bacteria, exacerbates IR and β cell dysfunction.
These interactions highlight the gut microbiota's integral role in the complex network of factors contributing to diabetes, making it a key target for therapeutic interventions.
Tryptophan metabolism by gut bacteria also influences diabetes, affecting glucagon-like peptide-1 secretion, β cell health, and systemic inflammation.
Dietary management, particularly high-fiber diets, can modulate gut microbiota, potentially improving metabolic outcomes in diabetes by reducing inflammation and enhancing microbial diversity.
Interaction between oral antidiabetic drugs and gut microbiota
Gut microbiota not only responds to antidiabetic medications but can also predict drug efficacy and adverse effects. For example, metformin alters the gut microbial composition, enriching beneficial SCFAs while also contributing to side effects. This dual effect of metformin is mediated through its influence on specific microbial populations, such as the enrichment of beneficial bacteria like Akkermansia muciniphila, which may help improve glucose tolerance, alongside an increase in potentially harmful Escherichia species that could contribute to gastrointestinal discomfort.
Other drugs like sodium glucose-like transporter 2 inhibitors and acarbose also interact with microbiota, influencing their therapeutic outcomes.
Therefore, the researchers suggest that gut microbiota should be considered in developing personalized antidiabetic treatments that optimize drug response and minimize side effects.
Therapeutic targeting of gut microbiota diversity
Given the role of gut microbiota in T2DM, therapies like prebiotics, probiotics, synbiotics, and fecal transplantation show promise.
These approaches are not without challenges, as the effectiveness of these therapies can vary widely depending on individual microbiota compositions and the specific strains used.
These approaches modulate gut bacteria to improve glucose control, insulin sensitivity, and metabolic profiles, offering potential adjunctive treatments to enhance efficacy and reduce side effects in diabetes management.
Conclusion
In conclusion, the gut microbiota plays a crucial role in the pathogenesis of T2DM, offering potential for personalized treatment strategies.
Despite the challenges in understanding microbial variability and establishing causality, ongoing research, and trials continue to refine our understanding and approach to microbiota-targeted therapies.
In the future, continued focus on identifying microbial signatures and refining interventions will be essential in advancing personalized medicine for diabetes.